Multimodal Imaging Approach in a Patient with Vogt-Koyanagi-Harada-like Syndrome Due to Dabrafenib and Trametinib Use for Cutaneous Melanoma.

PURPOSE: To describe a case of ocular inflammation associated with dabrafenib and trametinib chemotherapy for cutaneous melanoma by using a multimodal image approach. MATERIALS AND METHODS: We report on a 51-year-old woman with Vogt-Koyanagi-Harada-like syndrome, which occurred while she was undergoing treatment with dabrafenib and trametinib for cutaneous melanoma. The patient complained of sudden, bilateral vision loss of 2 days' duration. Anatomical and functional improvement was observed after administration of systemic steroids and cessation of chemotherapy. Later on, 6 weeks after restarting dabrafenib, she had an episode of granulomatous anterior uveitis, which was successfully managed with topical mydriatics and steroids. Strict follow-up with multimodal imaging was performed until recovery. CONCLUSIONS: This report emphasizes the importance of strict ophthalmological follow-up with multimodal imaging in patients receiving dabrafenib and trametinib, and the need for a multidisciplinary approach in the management of ocular inflammation during chemotherapy.

Post-Progression Treatments after Palbociclib plus Endocrine Therapy in HR+/HER2- Metastatic Breast Cancer Patients: What Is the Better Choice?

BACKGROUND: To date, a consensus has not yet been reached about the therapy sequence after disease progression (PD) on CDK4/6 inhibitors in patients with HR+/HER2- metastatic breast cancer (MBC). OBJECTIVES: The present study assesses, in a real-world setting, the activity of different subsequent therapies in patients who experienced a PD on palbociclib (P) + endocrine therapy (ET), to evaluate the best therapy sequence. METHODS: This is a multicenter retrospective observational study. Records of consecutive HR+/HER2- MBC patients from January 2017 to May 2019 were reviewed. The primary endpoint was the evaluation of progression-free survival (PFS) according to subsequent treatment lines after progression on P+ET. Toxicity data were also collected. RESULTS: The outcomes were analyzed in 89 MBC patients that had progressed on previous P+ET: 17 patients were on hormone therapy (HT) and 31 patients on chemotherapy (CT) as second-line treatments; seven patients were on HT and 34 on CT as third-line therapies. PFS of patients treated with HT as second-line therapy is significantly improved when compared with patients treated with CT (p=0.01). Considering third-line settings, the difference in PFS was not statistically different between HT and CT. A better outcome in terms of toxicity is observed among HT patients for both second- and third-line therapies. CONCLUSIONS: patients who were progressive on P+ET could still benefit from a subsequent ET. In patients who experienced a good efficacy from prior ET, without visceral metastatic sites, HT seems the most suitable option, when compared to CT, also in terms of safety.

PONDx: real-life utilization and decision impact of the 21-gene assay on clinical practice in Italy.

Clinicopathological prognostic features have limited value to identify with precision newly diagnosed patients with hormone receptor (HR)-positive, HER2-negative breast cancer (BC), who would benefit from chemotherapy (CT) in addition to adjuvant hormonal therapy (HT). The 21-gene Oncotype DX Breast Recurrence Score® (RS) assay has been demonstrated to predict CT benefit, hence supporting personalized decisions on adjuvant CT. The multicenter, prospective, observational study PONDx investigated the real-life use of RS® results in Italy and its impact on treatment decisions. Physicians' treatment recommendations (HT ± CT) were documented before and after availability of RS results, and changes in recommendations were determined. In the HR+ HER2- early BC population studied (N = 1738), physicians recommended CT + HT in 49% of patients pre-RS. RS-guided treatment decisions resulted in 36% reduction of CT recommendations. PONDx confirms that RS results provide clinically relevant information for CT recommendation in early-stage BC, resulting in a reduction of more than a third of CT use.

Baseline Characteristics and Outcomes of Cancer Patients Infected with SARS-CoV-2 in the Lombardy Region, Italy (AIOM-L CORONA): A Multicenter, Observational, Ambispective, Cohort Study.

Cancer patients may be at high risk of infection and poor outcomes related to SARS-CoV-2. Analyzing their prognosis, examining the effects of baseline characteristics and systemic anti-cancer active therapy (SACT) are critical to their management through the evolving COVID-19 pandemic. The AIOM-L CORONA was a multicenter, observational, ambispective, cohort study, with the intended participation of 26 centers in the Lombardy region (Italy). A total of 231 cases were included between March and September 2020. The median age was 68 years; 151 patients (62.2%) were receiving SACT, mostly chemotherapy. During a median follow-up of 138 days (range 12-218), 93 events occurred. Age ≥60 years, metastatic dissemination, dyspnea, desaturation, and interstitial pneumonia were all independent mortality predictors. Overall SACT had a neutral effect (Odds Ratio [OR] 0.83, 95%Confidence Interval [95%CI] 0.32-2.15); however, metastatic patients receiving SACT were less likely to die as compared to untreated counterparts, after adjusting for other confounding variables (OR 0.23, 95%CI 0.11-0.51, p < 0.001). Among cancer patients infected by SARS-CoV-2, those with metastases were most at risk of death, especially in the absence of SACT. During the ongoing pandemic, these vulnerable patients should avoid exposure to SARS-CoV-2, while treatment adjustments and prioritizing vaccination are being considered according to international recommendations.

Impact of Baseline and On-Treatment Glycemia on Everolimus-Exemestane Efficacy in Patients with Hormone Receptor-Positive Advanced Breast Cancer (EVERMET).

PURPOSE: The mTOR complex C1 (mTORC1) inhibitor everolimus in combination with the aromatase inhibitor exemestane is an effective treatment for patients with hormone receptor-positive (HR+), HER2-negative (HER2-), advanced breast cancer (HR+/HER2- aBC). However, everolimus can cause hyperglycemia and hyperinsulinemia, which could reactivate the PI3K/protein kinase B (AKT)/mTORC1 pathway and induce tumor resistance to everolimus. EXPERIMENTAL DESIGN: We conducted a multicenter, retrospective, Italian study to investigate the impact of baseline and on-treatment (i.e., during first 3 months of therapy) blood glucose levels on progression-free survival (PFS) in patients with HR+/HER2- aBC treated with everolimus-exemestane. RESULTS: We evaluated 809 patients with HR+/HER2- aBC treated with everolimus-exemestane as any line of therapy for advanced disease. When evaluated as dichotomous variables, baseline and on-treatment glycemia were not significantly associated with PFS. However, when blood glucose concentration was evaluated as a continuous variable, a multivariable model accounting for clinically relevant patient- and tumor-related variables revealed that both baseline and on-treatment glycemia are associated with PFS, and this association is largely attributable to their interaction. In particular, patients who are normoglycemic at baseline and experience on-treatment diabetes have lower PFS compared with patients who are already hyperglycemic at baseline and experience diabetes during everolimus-exemestane therapy (median PFS, 6.34 vs. 10.32 months; HR, 1.76; 95% confidence interval, 1.15-2.69; P = 0.008). CONCLUSIONS: The impact of on-treatment glycemia on the efficacy of everolimus-exemestane therapy in patients with HR+/HER2- aBC depends on baseline glycemia. This study lays the foundations for investigating novel therapeutic approaches to target the glucose/insulin axis in combination with PI3K/AKT/mTORC1 inhibitors in patients with HR+/HER2- aBC.

Nanoparticle albumin-bound paclitaxel/liposomal-encapsulated doxorubicin in HER2-negative metastatic breast cancer patients.

Aim: To investigate the toxicity of nab-paclitaxel (wNP)/nonpegylated liposome-encapsulated doxorubicin (wNPLD) combination in HER2-negative metastatic breast cancer (MBC) patients as first-line treatment. Materials & methods: Phase I, single-arm study in metastatic breast cancer patients naive to previous chemotherapy for advanced disease. A 3 + 3 dose-escalation design was used to determine the safety. Primary endpoints were the identification of dose-limiting toxicity and maximum tolerated dose. Results: In total, 12 patients (mean age: 52 years; median metastatic sites: 2) were enrolled and 97 cycles were completed. Maximum tolerated dose was wNP + wNPLD 25 mg/m2. The most common adverse events were neutropenia, nausea, diarrhea and mucositis. The objective response rate was 68% (response mean duration: 12.6 months). Conclusion: wNP/wNPLD combination constitutes an active regimen with mild toxicity.

Should All Patients With HR-Positive HER2-Negative Metastatic Breast Cancer Receive CDK 4/6 Inhibitor As First-Line Based Therapy? A Network Meta-Analysis of Data from the PALOMA 2, MONALEESA 2, MONALEESA 7, MONARCH 3, FALCON, SWOG and FACT Trials.

Background: We aim to understand whether all patients with hormonal receptor (HR)-positive (+)/human epidermal growth factor receptor-2 (HER2)-negative (-) metastatic breast cancer (MBC) should receive cyclin D-dependent kinase (CDK) 4/6 inhibitor-based therapy as a first-line approach. METHODS: A network meta-analysis (NMA) using the Bayesian hierarchical arm-based model, which provides the estimates for various effect sizes, were computed. RESULTS: First-line treatment options in HR+/HER2- MBC, including CDK 4/6 inhibitors combined with aromatase inhibitors (AIs) or fulvestrant (F), showed a significantly longer progression-free survival (PFS) in comparison with AI monotherapy, with a total of 26% progression risk reduction. In the indirect comparison across the three classes of CDK 4/6 inhibitors and F endocrine-based therapies, the first strategy resulted in longer PFS, regardless of specific CDK 4/6 inhibitor (HR: 0.68; 95% CrI: 0.53-0.87 for palbociclib + AI, HR: 0.65; 95% CrI: 0.53-0.79 for ribociclib + AI, HR: 0.63; 95% CrI: 0.47-0.86 for abemaciclib + AI) and patient's characteristics. Longer PFS was also found in patients with bone-only and soft tissues limited disease treated with CDK 4/6 inhibitors. CONCLUSIONS: CDK 4/6 inhibitors have similar efficacy when associated with an AI in the first-line treatment of HR+ MBC, and are superior to either F or AI monotherapy, regardless of any other patients or tumor characteristics.

[LHRH analogs: current role in early and advanced breast cancer treatment of premenopausal patients.] / Gli analoghi LHRH: l'attuale ruolo nel trattamento del carcinoma mammario nella fase di malattia precoce e avanzata.

LHRH analogues (LHRHa) are used in the treatment of breast cancer that occurs in young women. Amenorrhoea induced by chemotherapy correlates with a reduced risk of recurrence disease. In premenopausal women, analogous LHRHs are used to suppress ovarian estrogen production, raising estrogen hormone levels to post-menopausal values and improving patient outcomes. Two large clinical studies have investigated the role of complete estrogen blockage in adjuvant hormonal treatment of premenopausal patients. Both studies showed the clinical benefit of ovarian suppression treatment, mainly associated with non-steroidal aromatase inhibitor exemestane in high-risk patients. In the recent years, hormonal treatments made available in clinical practice have considerably prolonged the median survival of patients suffering from endocrine-responsive metastatic breast cancer. Even in the premenopausal setting, CDK4/6 inhibitors in association with endocrine therapy have shown a marked improvement in patient outcomes. The safety and efficacy of this new class of drugs demonstrated in the MONALEESA-7 study in premenopausal women and in the premenopausal subgroups of the PALOMA-3 and MONARCH 2 studies support the use of hormone therapy and analogous LHRH combined with CDK 4/6 inhibitor in patients in premenopausal. Finally, LHRH analogues have been extensively studied in strategies for maintaining ovarian function and fertility preservation during adjuvant chemotherapy in younger patients.

T-DM1 and brain metastases: Clinical outcome in HER2-positive metastatic breast cancer.

BACKGROUND: We reported the results of an Italian large retrospective analysis that evaluated the effectiveness and safety of T-DM1 in 'field-practice' breast cancer patients. We performed a sub-analysis to investigate the clinical activity of T-DM1 in patients with brain metastases (BMs). METHODS: The records of 87 adult women with HER2-positive breast cancer and BMs treated with T-DM1 were reviewed. Their clinical outcomes were compared with those of 216 patients without central nervous system (CNS) involvement. RESULTS: Response to T-DM1 treatment in BMs was available for 53 patients in the BM group (60.9%): two patients reported a complete response (3.8%), 11 patients obtained partial response (20.7%; overall response rate: 24.5%), 16 patients had a stable disease (30.1%). Regarding extracranial disease, a total of 77 and 191 patients were evaluable for response in BM group and non-BM group, respectively. The overall response rate was 35.1% in the BM group and 38.3% in the non-BM group; disease control rate was 53.3% and 66.6%, respectively. At a median follow-up of 16 months (range: 1-55), median cumulative progression-free survival (PFS) was 7 months (95% CI: 5.4-8.6) in the BM group and 8 months (95% CI: 5.7-10.3) in the non-BM group. In the second-line setting, PFS was 5 (95% CI: 3.1-6.9) versus 11 (95% CI: 7.1-14.9) months (p = 0.01). Overall survival was 14 months (95% CI: 12.2-15.8) in the BM group and 32 months (95% CI: 24.4-39.6) in the non-BM group (p < 0.0001). CONCLUSIONS: T-DM1 is active in breast cancer patients with BMs.

Short-term benefit of smoking cessation along with glycopirronium on lung function and respiratory symptoms in mild COPD patients: a retrospective study.

INTRODUCTION: Tobacco smoke is the leading cause of chronic obstructive pulmonary disease (COPD). Smoking cessation can change the natural history of COPD, as we know from the GOLD guidelines. Little is known about the short-term clinical and functional effects of smoking cessation treatment combined with anti-muscarinic bronchodilators. OBJECTIVE: To determine whether quitting smoking, obtained by smoking cessation treatment combined with the use of a new long-acting muscarinic antagonist bronchodilator (LAMA), can improve lung function tests and respiratory symptoms more than the use of LAMA alone. METHODS: We evaluated, in a retrospective analysis, the functional and clinical data, collected in one year, of 120 patients who were current smokers affected by mild COPD and who quit smoking using smoking cessation treatment combined with glycopirronium. We compared them with a group of 80 patients with mild COPD undergoing the same treatment but who did not quit smoking. All patients underwent functional and clinical tests at baseline and at a third-month check. MEASUREMENTS AND MAIN RESULTS: The two groups were homogeneous in terms of demographic data without significant differences. All patients used varenicline for smoking cessation. They all performed the following tests: a spirometry with detection of resistances, the 6 min walking test, haemogasanalysis, the exhaled CO test, the COPD assessment test (CAT) and finally the modified Medical Research Council test (mMRC). A significant improvement in the functional tests at the third-month check was found in both groups-quitters and non-quitters. However, a notable increase in the examined parameters was registered in the group of patients who quit smoking, in particular, we observed a significant increase at the third-month check of the parameter forced expiratory volume in 1 s (FEV1) of more than 200 ml with p < 0.001. A comparison between quitters and non-quitters revealed a major benefit derived from smoking cessation in terms of functional changes and symptom relief. In particular, not only FEV1 but also forced expiratory flow at 25%-75% of vital capacity (FEF 25-75) (p < 0.01) and CAT (p < 0.001) were found to be significantly improved in patients who quit than in patients who did not at the check time point. CONCLUSIONS: Smoking cessation treatment obtained by varenicline was confirmed as a crucial therapeutic option, especially when combined with bronchodilator in mild COPD. Patients who quit smoking could already benefit from both treatments in the short term, improving lung function and respiratory symptoms and therefore improving their quality of life.

Activity of Eribulin Mesylate in Brain Metastasis from Breast Cancer: A Stone in a Pond?

BACKGROUND: Brain metastases develop in approximately 10-25% of patients with metastatic breast cancer (MBC) and are associated with a very poor prognosis. CASE REPORT: We report the case of a 40-year-old woman with MBC and associated lung, bone, liver, and brain metastases, who experienced a time to progression of several months with eribulin after whole-brain radiotherapy (WBRT), 2 lines of chemotherapy, and 1 line of hormonal therapy, maintaining a good toxicity profile. DISCUSSION: Eribulin, in association with local treatment such as WBRT, can be well tolerated and effective in achieving a long progression-free survival and a good control of brain metastases in patients with MBC who have received multiple lines of treatment. The vascular remodeling properties of eribulin, combined with brain radiotherapy, might facilitate the passage of eribulin across the blood brain barrier, improving brain response. CONCLUSION: Our anecdotal experience suggests that eribulin may have a potentially beneficial effect on brain metastases while maintaining a good systemic control of the disease in patients with MBC.

Body Mass Index as a Risk Factor for Toxicities in Patients with Advanced Soft-Tissue Sarcoma Treated with Trabectedin.

OBJECTIVES: Low body mass index (BMI) and/or low lean body mass have been shown to be risk factors for chemotherapy-related toxicities in a number of different cancers. However, no data are available regarding the role of BMI as a risk factor for developing toxicities related to the novel anticancer agent, trabectedin, in patients with soft-tissue sarcoma (STS). We evaluated the role of BMI as a risk factor for trabectedin-related toxicity in patients with STS. METHODS: Data from 51 patients with metastatic/advanced STS treated with trabectedin after progression on ≥1 anthracycline ± ifosfamide regimen were retrospectively reviewed. RESULTS: Eighteen patients (35.3%) were underweight, and the remainder were of normal bodyweight (45.1%) or overweight (19.6%). Neutropenia of any grade (77.8 vs. 33.3%) and grade 3-4 neutropenia (50.0 vs. 18.2%) occurred more frequently in the underweight versus normal/overweight patients (p = 0.025). Febrile neutropenia also occurred more frequently in underweight patients. Differences remained statistically significant after adjusting for other predictors of toxicity. There were no significant differences in other hematological and nonhematological toxicities between the groups. CONCLUSIONS: The data suggest for the first time that BMI should be considered a risk factor for neutropenia in patients with STS treated with trabectedin.

Drug-induced hepatotoxicity in cancer patients - implication for treatment.

INTRODUCTION: All anticancer drugs can cause idiosyncratic liver injury. Therefore, hepatoprotective agents assume particular importance to preserve liver function. Hepatic injury represents 10% of cases of acute hepatitis in adults; drug-related damage is still misjudged because of relative clinical underestimation and difficult differential diagnosis. Chemotherapeutic agents can produce liver toxicity through different pathways, resulting in different categories of liver injuries, but these drugs are not homogeneously hepatotoxic. Frequently, anticancer-induced hepatotoxicity is idiosyncratic and influenced by multiple factors. AREAS COVERED: The aim of this paper is to perform a review of the literature regarding anticancer-induced liver toxicity. We described hepatotoxicity mechanisms of principal anticancer agents and respective dose reductions. Furthermore, we reviewed studies on hepatoprotectors and their optimal use. Tiopronin, magnesium isoglycyrrhizinate and S-Adenosylmethionine (AdoMet) demonstrated, in some small studies, a potential hepatoprotective activity. EXPERT OPINION: Actually, in the literature only small experiences are reported. Even though hepatoprotective agents seem to be useful in the oncologic setting, the lack of well-designed prospective Phase III randomized controlled trials is a major limit in the introduction of hepatoprotectors in cancer patients and these kind of studies are warranted to support their use and to give further recommendations for the clinical practice.

Analysis of germline gene copy number variants of patients with sporadic pancreatic adenocarcinoma reveals specific variations.

OBJECTIVES: The rapid fatality of pancreatic cancer is, in large part, the result of diagnosis at an advanced stage in the majority of patients. Identification of individuals at risk of developing pancreatic adenocarcinoma would be useful to improve the prognosis of this disease. There is presently no biological or genetic indicator allowing the detection of patients at risk. Our main goal was to identify copy number variants (CNVs) common to all patients with sporadic pancreatic cancer. METHODS: We analyzed gene CNVs in leukocyte DNA from 31 patients with sporadic pancreatic adenocarcinoma and from 93 matched controls. Genotyping was performed with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). RESULTS: We identified 431 single nucleotide polymorphism (SNP) probes with abnormal hybridization signal present in the DNA of all 31 patients. Of these SNP probes, 284 corresponded to 3 or more copies and 147 corresponded to 1 or 0 copies. Several cancer-associated genes were amplified in all patients. Conversely, several genes supposed to oppose cancer development were present as single copy. CONCLUSIONS: These data suggest that a set of 431 CNVs could be associated with the disease. This set could be useful for early diagnosis.