Characterization of HER2-low breast cancer in young women with germline BRCA1/2 pathogenetic variants: Results of a large international retrospective cohort study.

BACKGROUND: Breast cancer (BC) in women aged ≤40 years carrying germline pathogenetic variants (PVs) in BRCA1/2 genes is infrequent but often associated with aggressive features. Human epidermal growth factor receptor 2 (HER2)-low-expressing BC has recently emerged as a novel therapeutic target but has not been characterized in this rare patient subset. METHODS: Women aged ≤40 years with newly diagnosed early-stage HER2-negative BC (HER2-0 and HER2-low) and germline BRCA1/2 PVs from 78 health care centers worldwide were retrospectively included. Chi-square test and Student t-test were used to describe variable distribution between HER2-0 and HER2-low. Associations with HER2-low status were assessed with logistic regression. Kaplan-Meier method and Cox regression analysis were used to assess disease-free survival (DFS) and overall survival. Statistical significance was considered for p ≤ .05. RESULTS: Of 3547 included patients, 32.3% had HER2-low BC, representing 46.3% of hormone receptor-positive and 21.3% of triple-negative (TN) tumors. HER2-low vs. HER2-0 BC were more often of grade 1/2 (p < .001), hormone receptor-positive (p < .001), and node-positive (p = .003). BRCA2 PVs were more often associated with HER2-low than BRCA1 PVs (p < .001). HER2-low versus HER2-0 showed better DFS (hazard ratio [HR], 0.86; 95% CI, 0.76-0.97) in the overall population and more favorable DFS (HR, 0.78; 95% CI, 0.64-0.95) and overall survival (HR, 0.65; 95% CI, 0.46-0.93) in the TN subgroup. Luminal A-like tumors in HER2-low (p = .014) and TN and luminal A-like in HER2-0 (p = .019) showed the worst DFS. CONCLUSIONS: In young patients with HER2-negative BC and germline BRCA1/2 PVs, HER2-low disease was less frequent than expected and more frequently linked to BRCA2 PVs and associated with luminal-like disease. HER2-low status was associated with a modestly improved prognosis.

Progressive multifocal leukoencephalopathy, advanced ductal breast carcinoma, systemic sclerosis, and checkpoint inhibitors: a therapeutic dilemma.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating central nervous system disease infection by JC virus (JCV) in patients with a significant decline in cellular immunity. No specific treatment has demonstrated efficacy, and the disease progresses to death in most patients. Recent findings have shown stabilization or improvement of PML lesions after treatment with checkpoint inhibitors (CPI) based on immune reconstitution. Nevertheless, immunotherapy may specifically cause autoimmune diseases or may deteriorate pre-existing ones. We report a case of a patient under treatment for advanced ductal breast carcinoma and systemic sclerosis, who developed PML. The therapeutic approach included withdrawal of drugs with possible immunosuppressive effect and treatment with pembrolizumab. In the absence of reliable markers to predict CPIs response and a concern for an autoimmune worsening, immunotherapy was administered late in the course of the disease. Finally, she did not experience an autoimmune disease flare-up; however, pembrolizumab could not prevent disease progression. We believe that potential autoimmune complications should not delay treatment initiation with CPIs in PML.

Randomized Phase 0/I Trial of the Mitochondrial Inhibitor ME-344 or Placebo Added to Bevacizumab in Early HER2-Negative Breast Cancer.

PURPOSE: We previously demonstrated that mitochondrial inhibitors' efficacy was restricted to a metabolic context in which mitochondrial respiration was the predominant energy source, a situation achievable by inducing vascular normalization/hypoxia correction with antiangiogenics. Vascular normalization can be tracked with 2[18F]fluoro-2-deoxy-d-glucose (FDG)-PET. We tested the efficacy of the mitochondrial inhibitor ME-344 or placebo added to bevacizumab in early breast cancer. PATIENTS AND METHODS: Treatment-naïve HER2-negative patients with T > 1 cm (any N) underwent a breast-centered 18F-fluorodeoxyglucose (FDG)-PET (day 1) and received a single dose of bevacizumab (15 mg/kg), followed by a second FDG-PET (day 8). Patients were then randomized (1:1) to Arm A (ME-344 10 mg/kg intravenous on days 8, 15, and 21) or Arm B (placebo). Tumors were biopsied on days 0 and 29. Succinate dehydrogenase enzyme histochemistry (SDH-EHC), confocal microscopy of vessel architecture, and HIF1α staining were performed in pre- and posttreatment biopsies to assess the pharmacodynamics, vessel normalization, and tissue re-oxygenation by bevacizumab, respectively. RESULTS: ME-344 displayed significant biological activity versus placebo: compared with a 186% increase in Arm B, Ki67 decreased by 23.4% from days 0 to 28 in Arm A (P < 0.001) (N = 42 patients). FDG-PET predicted vascular normalization in about one-third of the patients in each arm, which was confirmed using confocal microscopy and HIF1α staining. In the subgroup with vascular normalization, ME-344 induced a Ki67 decrease of 33.4% (placebo: 11.8 increase). SDH-EHC suggested on-target effects of ME-344. CONCLUSIONS: ME-344 has significant biological antitumor activity in HER2-negative breast cancer, particularly after induction of vascular normalization and tissue reoxygenation with bevacizumab.

Maintenance with Trabectedin in the Treatment of Platinum-Sensitive Recurrent Ovarian Cancer.

Ovarian cancer is the seventh most common type of cancer and the fifth leading cause of cancer death among women worldwide. The current usual therapeutic approach in this disease includes optimal cytoreductive therapy followed by platinum-based adjuvant chemotherapy, along with neoadjuvant chemotherapy prior to surgery in selected cases. The platinum-free interval (PFI) continues to be the most useful tool to assist in the selection of the subsequent therapy and to predict response to treatment. The combination of trabectedin and pegylated liposomal doxorubicin (PLD) is useful in patients with partially platinum-sensitive recurrent ovarian cancer, in patients who have previously received two or more platinum-based chemotherapy regimens, in patients who have already experienced a platinum-induced hypersensitivity reaction and in patients who have previously failed to respond to a platinum-based treatment. CASE PRESENTATION: A 64-years-old postmenopausal woman with pain, abdominal distension, and an altered intestinal transit and with partially platinum-sensitive recurrent ovarian cancer, was successfully treated with a second line of trabectedin chemotherapy in combination with PLD, followed by trabectedin in monotherapy. This case proves the effectiveness of the combination of trabectedin and PLD and demonstrates how the administration of trabectedin, even in monotherapy, allows to maintain an adequate clinical response with good tolerance to the treatment during more than two years of drug administration.

ROLE OF PARENTERAL NUTRITION IN ONCOLOGIC PATIENTS WITH INTESTINAL OCCLUSION AND PERITONEAL CARCINOMATOSIS.

INTRODUCTION AND AIMS: the precise role of parenteral nutrition in the management of oncologic patients with intestinal occlusion is not well defined yet. We aimed to identify the effects of parenteral nutrition in these patients regarding prognosis. MATERIAL AND METHODS: 55 patients with intestinal occlusion and peritoneal carcinomatosis were included. Parenteral nutrition aimed at 20-35 kcal/Kg/day, and 1.0 g/kg/day of amino-acids. Weight, body mass index, type of tumor, type of chemotherapy, and ECOG among others were recorded and analyzed. RESULTS: 69.1% of the patients had gastrointestinal tumors, 18.2% gynecologic and 12.7% others. Age was 60 ± 13y, baseline ECOG 1.5 ± 0.5 and body mass index 21.6 ± 4.3. Malnutrition was present in 85%. Survival from the start of parenteral nutrition was not significant when considering baseline ECOG (log rank = 0.593, p = 0.743), previous lines of chemotherapy (log rank = 2.117, p = 0.548), baseline BMI (log rank = 2.686, p = 0.261), or type of tumor (log rank = 2.066, p = 0.356). Survival in patients who received home parenteral nutrition after hospital discharge was higher than those who stayed in-hospital (log rank = 7.090, p = 0.008). Survival in patients who started chemotherapy during or after parenteral nutrition was higher than those who did not so (log rank = 17.316, p < 0.001). A total of 3.6% of patients presented catheter related infection without affecting survival (log rank = 0.061, p = 0.804). CONCLUSIONS: Parenteral nutrition in patients with advanced cancer and intestinal occlusion is safe, and in tho se who respond to chemotherapy, further administration of home parenteral nutrition together with chemotherapy may enhance prolonged survival.

Introducción y objetivos: el papel preciso de la nutrición parenteral en el manejo de los pacientes oncológicos con obstrucción intestinal no está bien definido todavía. El objetivo del presente trabajo es evaluar los efectos de la nutrición parenteral en este tipo de pacientes en cuanto al pronóstico. Material y métodos: fueron incluidos 55 pacientes con obstrucción intestinal y carcinomatosis peritoneal. La nutrición parenteral proporcionó 20-35 kcal/Kg/día y 1.0 g/kg/día de aminoácidos. El peso, el IMC, el tipo de tumor, el tipo de quimioterapia recibida y el ECOG, entre otras variables, fueron recogidas y analizadas. Resultados: un 69,1% de los pacientes presentaban tumors gastrointestinales, un 18,2% ginecológicos y otros tumores el 12,7% restante. La edad media fue de 60 ± 13 años, con un ECOG basal de 1,5 ± 0,5 y un IMC de 21,6 ± 4,3. La presencia de malnutrición fue de un 85%. La supervivencia desde el inicio de la nutrición parenteral no fue significativamente distinta entre los pacientes al considerar su ECOG basal (log rank = 0,593, p = 0,743), las líneas previas de quimioterapia recibida (log rank = 2,117, p = 0,548), el IMC basal (log rank = 2,686, p = 0,261), o el tipo de tumor (log rank = 2,066, p = 0,356). La supervivencia en los pacientes en que fue posible el alta hospitalaria con nutrición parenteral fue superior (log rank = 7,090, p = 0,008). La supervivencia en los pacientes en que se inició la quimioterapia durante o tras iniciar la nutrición parenteral fue también superior (log rank = 17,316, p < 0,001). Un total de 3,6% de los pacientes presentaron infección relacionada con el catéter sin afectar la supervivencia (log rank = 0,061, p = 0,804). Conclusión: la nutrición parenteral en los pacientes oncológicos con obstrucción intestinal y carcinomatosis peritoneal es segura y, en aquellos que responden a qui mioterapia, el uso de la nutrición parenteral domiciliaria, junto con en tratamiento antitumoral activo, aumentan la supervivencia.

Role of parenteral nutrition in oncologic patients with intestinal occlusion and peritoneal carcinomatosis / Papel de la nutrición parenteral en pacientes oncológicos con oclusión intestinal y carcinomatosis peritoneal

Introduction and aims: the precise role of parenteral nutrition in the management of oncologic patients with intestinal occlusion is not well defined yet. We aimed to identify the effects of parenteral nutrition in these patients regarding prognosis. Material and methods: 55 patients with intestinal occlusion and peritoneal carcinomatosis were included. Parenteral nutrition aimed at 20-35 kcal/Kg/day, and 1.0 g/kg/day of amino-acids. Weight, body mass index, type of tumor, type of chemotherapy, and ECOG among others were recorded and analyzed. Results: 69.1% of the patients had gastrointestinal tumors, 18.2% gynecologic and 12.7% others. Age was 60 ± 13y, baseline ECOG 1.5 ± 0.5 and body mass index 21.6 ± 4.3. Malnutrition was present in 85%. Survival from the start of parenteral nutrition was not significant when considering baseline ECOG (log rank = 0.593, p = 0.743), previous lines of chemotherapy (log rank = 2.117, p = 0.548), baseline BMI (log rank = 2.686, p = 0.261), or type of tumor (log rank = 2.066, p = 0.356). Survival in patients who received home parenteral nutrition after hospital discharge was higher than those who stayed in-hospital (log rank = 7.090, p = 0.008). Survival in patients who started chemotherapy during or after parenteral nutrition was higher than those who did not so (log rank = 17.316, p < 0.001). A total of 3.6% of patients presented catheter related infection without affecting survival (log rank = 0.061, p = 0.804). Conclusions: Parenteral nutrition in patients with advanced cancer and intestinal occlusion is safe, and in those who respond to chemotherapy, further administration of home parenteral nutrition together with chemotherapy may enhance prolonged survival (AU)

Introducción y objetivos: el papel preciso de la nutrición parenteral en el manejo de los pacientes oncológicos con obstrucción intestinal no está bien definido todavía. El objetivo del presente trabajo es evaluar los efectos de la nutrición parenteral en este tipo de pacientes en cuanto al pronóstico. Material y métodos: fueron incluidos 55 pacientes con obstrucción intestinal y carcinomatosis peritoneal. La nutrición parenteral proporcionó 20-35 kcal/Kg/día y 1.0 g/kg/día de aminoácidos. El peso, el IMC, el tipo de tumor, el tipo de quimioterapia recibida y el ECOG, entre otras variables, fueron recogidas y analizadas. Resultados: un 69,1% de los pacientes presentaban tumors gastrointestinales, un 18,2% ginecológicos y otros tumores el 12,7% restante. La edad media fue de 60 ± 13 años, con un ECOG basal de 1,5 ± 0,5 y un IMC de 21,6 ± 4,3. La presencia de malnutrición fue de un 85%. La supervivencia desde el inicio de la nutrición parenteral no fue significativamente distinta entre los pacientes al considerar su ECOG basal (log rank = 0,593, p = 0,743), las líneas previas de quimioterapia recibida (log rank = 2,117, p = 0,548), el IMC basal (log rank = 2,686, p = 0,261), o el tipo de tumor (log rank = 2,066, p = 0,356). La supervivencia en los pacientes en que fue posible el alta hospitalaria con nutrición parenteral fue superior (log rank = 7,090, p = 0,008). La supervivencia en los pacientes en que se inició la quimioterapia durante o tras iniciar la nutrición parenteral fue también superior (log rank = 17,316, p < 0,001). Un total de 3,6% de los pacientes presentaron infección relacionada con el catéter sin afectar la supervivencia (log rank = 0,061, p = 0,804). Conclusión: la nutrición parenteral en los pacientes oncológicos con obstrucción intestinal y carcinomatosis peritoneal es segura y, en aquellos que responden a quimioterapia, el uso de la nutrición parenteral domiciliaria, junto con en tratamiento antitumoral activo, aumentan la supervivencia (AU)