ESGO-ESMO-ESP consensus conference recommendations on ovarian cancer: pathology and molecular biology and early, advanced and recurrent disease.

The European Society of Gynaecological Oncology, the European Society for Medical Oncology (ESMO) and the European Society of Pathology held a consensus conference (CC) on ovarian cancer on 15-16 June 2022 in Valencia, Spain. The CC panel included 44 experts in the management of ovarian cancer and pathology, an ESMO scientific advisor and a methodologist. The aim was to discuss new or contentious topics and develop recommendations to improve and harmonise the management of patients with ovarian cancer. Eighteen questions were identified for discussion under four main topics: (i) pathology and molecular biology, (ii) early-stage disease and pelvic mass in pregnancy, (iii) advanced stage (including older/frail patients) and (iv) recurrent disease. The panel was divided into four working groups (WGs) to each address questions relating to one of the four topics outlined above, based on their expertise. Relevant scientific literature was reviewed in advance. Recommendations were developed by the WGs and then presented to the entire panel for further discussion and amendment before voting. This manuscript focuses on the recommendation statements that reached a consensus, their voting results and a summary of evidence supporting each recommendation.

Safety of assisted reproductive techniques in young women harboring germline pathogenic variants in BRCA1/2 with a pregnancy after prior history of breast cancer.

BACKGROUND: Knowledge is growing on the safety of assisted reproductive techniques (ART) in cancer survivors. No data exist, however, for the specific population of breast cancer patients harboring germline BRCA1/2 pathogenic variants. PATIENTS AND METHODS: This is a multicenter retrospective cohort study across 30 centers worldwide including women diagnosed at ≤40 years with stage I-III breast cancer, between January 2000 and December 2012, harboring known germline BRCA1/2 pathogenic variants. Patients included in this analysis had a post-treatment pregnancy either achieved through use of ART (ART group) or naturally (non-ART group). ART procedures included ovulation induction, ovarian stimulation for in vitro fertilization or intracytoplasmic sperm injection, and embryo transfer under hormonal replacement therapy. RESULTS: Among the 1424 patients registered in the study, 168 were eligible for inclusion in the present analysis, of whom 22 were in the ART group and 146 in the non-ART group. Survivors in the ART group conceived at an older age compared with those in the non-ART group (median age: 39.7 versus 35.4 years, respectively). Women in the ART group experienced more delivery complications compared with those in the non-ART group (22.1% versus 4.1%, respectively). No other apparent differences in obstetrical outcomes were observed between cohorts. The median follow-up from pregnancy was 3.4 years (range: 0.8-8.6 years) in the ART group and 5.0 years (range: 0.8-17.6 years) in the non-ART group. Two patients (9.1%) in the ART group experienced a disease-free survival event (specifically, a locoregional recurrence) compared with 40 patients (27.4%) in the non-ART group. In the ART group, no patients deceased compared with 10 patients (6.9%) in the non-ART group. CONCLUSION: This study provides encouraging safety data on the use of ART in breast cancer survivors harboring germline pathogenic variants in BRCA1/2, when natural conception fails or when they opt for ART in order to carry out preimplantation genetic testing.

Olaparib in combination with pegylated liposomal doxorubicin for platinum-resistant ovarian cancer regardless of BRCA status: a GEICO phase II trial (ROLANDO study).

BACKGROUND: There is limited evidence for the benefit of olaparib in platinum-resistant ovarian cancer (PROC) patients with BRCA wild-type tumors. This study investigated whether this combination of a DNA-damaging chemotherapy plus olaparib is effective in PROC regardless BRCA status. PATIENTS AND METHODS: Patients with high-grade serous or endometrioid ovarian carcinoma and one previous PROC recurrence were enrolled regardless of BRCA status. Patients with ≤4 previous lines (up to 5 in BRCA-mut) with at least one previous platinum-sensitive relapse were included; primary PROC was allowed only in case of BRCA-mut. Patients initially received six cycles of olaparib 300 mg b.i.d. (biduum) + intravenous pegylated liposomal doxorubicin (PLD) 40 mg/m2 (PLD40) every 28 days, followed by maintenance with olaparib 300 mg b.i.d. until progression or toxicity. The PLD dose was reduced to 30 mg/m2 (PLD30) due to toxicity. The primary endpoint was progression-free survival (PFS) at 6 months (6m-PFS) by RECIST version 1.1. A proportion of 40% 6m-PFS or more was considered of clinical interest. RESULTS: From 2017 to 2020, 31 PROC patients were included. BRCA mutations were present in 16%. The median of previous lines was 2 (range 1-5). The overall disease control rate was 77% (partial response rate of 29% and stable disease rate of 48%). After a median follow-up of 10 months, the 6m-PFS and median PFS were 47% and 5.8 months, respectively. Grade ≥3 treatment-related adverse events occurred in 74% of patients, with neutropenia/anemia being the most frequent. With PLD30 serious AEs were less frequent than with PLD40 (21% versus 47%, respectively); moreover, PLD30 was associated with less PLD delays (32% versus 38%) and reductions (16% versus 22%). CONCLUSIONS: The PLD-olaparib combination has shown significant activity in PROC regardless of BRCA status. PLD at 30 mg/m2 is better tolerated in the combination.

SEOM clinical guideline in ovarian cancer (2020)

Despite remarkable advances in the knowledge of molecular biology and treatment, ovarian cancer remains the leading cause of death from gynecologic cancer. In the last decade, there have been important advances both in systemic and surgical treatment. However, there is no doubt that the incorporation of PARP inhibitors as maintenance after the response to platinum-based chemotherapy, first in recurrent disease and recently also in first line, will change the natural history of the disease. The objective of this guide is to summarize the current evidence for the diagnosis, treatment, and follow-up of ovarian cancer, and to provide evidence-based recommendations for clinical practice (AU)

SEOM clinical guideline in ovarian cancer (2020).

Despite remarkable advances in the knowledge of molecular biology and treatment, ovarian cancer remains the leading cause of death from gynecologic cancer. In the last decade, there have been important advances both in systemic and surgical treatment. However, there is no doubt that the incorporation of PARP inhibitors as maintenance after the response to platinum-based chemotherapy, first in recurrent disease and recently also in first line, will change the natural history of the disease.The objective of this guide is to summarize the current evidence for the diagnosis, treatment, and follow-up of ovarian cancer, and to provide evidence-based recommendations for clinical practice.

BEECH: a dose-finding run-in followed by a randomised phase II study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with paclitaxel in patients with estrogen receptor-positive advanced or metastatic breast cancer, and in a PIK3CA mutant sub-population.

BACKGROUND: BEECH investigated the efficacy of capivasertib (AZD5363), an oral inhibitor of AKT isoforms 1-3, in combination with the first-line weekly paclitaxel for advanced or metastatic estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, and in a phosphoinositide 3-kinase, catalytic, alpha polypeptide mutation sub-population (PIK3CA+). PATIENTS AND METHODS: BEECH consisted of an open-label, phase Ib safety run-in (part A) in 38 patients with advanced breast cancer, and a randomised, placebo-controlled, double-blind, phase II expansion (part B) in 110 women with ER+/HER2- metastatic breast cancer. In part A, patients received paclitaxel 90 mg/m2 (days 1, 8 and 15 of a 28-day cycle) with capivasertib taken twice daily (b.i.d.) at two intermittent ascending dosing schedules. In part B, patients were randomly assigned, stratified by PIK3CA mutation status, to receive paclitaxel with either capivasertib or placebo. The primary end point for part A was safety to recommend a dose and schedule for part B; primary end points for part B were progression-free survival (PFS) in the overall and PIK3CA+ sub-population. RESULTS: Capivasertib was well tolerated, with a 400 mg b.i.d. 4 days on/3 days off treatment schedule selected in part A. In part B, median PFS in the overall population was 10.9 months with capivasertib versus 8.4 months with placebo [hazard ratio (HR) 0.80; P = 0.308]. In the PIK3CA+ sub-population, median PFS was 10.9 months with capivasertib versus 10.8 months with placebo (HR 1.11; P = 0.760). Based on the Common Terminology Criteria for Adverse Event v4.0, the most common grade ≥3 adverse events in the capivasertib group were diarrhoea, hyperglycaemia, neutropoenia and maculopapular rash. Dose intensity of paclitaxel was similar in both groups. CONCLUSIONS: Capivasertib had no apparent impact on the tolerability and dose intensity of paclitaxel. Adding capivasertib to weekly paclitaxel did not prolong PFS in the overall population or PIK3CA+ sub-population of ER+/HER2- advanced/metastatic breast cancer patients.ClinicalTrials.gov: NCT01625286.

Subcutaneous trastuzumab: drug development and current position.

HER2-positive breast cancer, accounting for 15 % of the total breast cancer patient population, carries in itself a bad prognosis, which has now become much better after the advent of anti-HER2 drugs. HER2-targeted therapy has significantly improved disease free- and overall survival in HER2-positive breast cancer, and has rendered better disease control both in the early and advanced disease setting. Trastuzumab treatment duration is often prolonged and poses significant time and resource challenges both on the treatment institutions and on the patient. The recent development of a subcutaneous formulation has meant a significant advance in this respect. We review the drug development of the compound and the current evidence on its use.

Retrospective analysis of the use of G-CSF and its impact on dose response for anthracycline plus taxane-based schedules in early breast cancer.

PURPOSE: To evaluate the impact on survival of the relative dose intensity (RDI) achieved in patients with early breast cancer receiving anthracycline plus taxane-based chemotherapy in the adjuvant setting. PATIENTS AND METHODS: Patients with early breast cancer diagnosed from January 1999 through December 2006 were included. Dose intensity was evaluated according to the number of delayed cycles and days and the percentage of RDI. RESULTS: A total of 231 breast cancer patients were included. Granulocyte colony-stimulating factor (G-CSF) was given to 39 % of patients. Few patients delayed chemotherapy administration ≥2 cycles (6 %) and ≥15 days (2 %), and the majority of them received ≥85 % of the RDI (98 %). Overall survival was statistically lower at 5 years in patients who received <85 % of RDI in comparison with those who received ≥85 % of RDI (80 vs. 97 %; p = 0.026). CONCLUSIONS: With a wide use of G-CSF in patients treated with adjuvant anthracyclines plus taxane-based schedules, 98 % of patients received a RDI ≥85 %. A significant although inconsistent impairment of survival was found in those patients with lower RDI.

Current questions for the treatment of advanced gastric cancer.

BACKGROUND: Gastric cancer remains a major health problem worldwide. Treatment of advanced gastric cancer is controversial and there is no standard regimen for first- or second-line chemotherapy (CT). This review aims to give an overview of the hot topics concerning treatment, prognostic factors and new strategies in advanced gastric cancer. MATERIAL AND METHODS: Seven questions of special clinical interest have been formulated previously to the literature review. With the aim of answering each of these questions, a specific search of the relevant trials and meta-analyses published or communicated from 1990 to date was performed. RESULTS: Patients treated with CT have a survival benefit over those treated with only best supportive care (BSC). Such active cytotoxic drugs as cisplatin or docetaxel and targeted agents as trastuzumab showed superiority in randomized trials. Other agents such as oxaliplatin, oral fluoropyrimidines and irinotecan showed non-inferiority or less toxic results, positioning them as valuable alternatives to classical schedules. Combination regimens seem to be an improvement over single agent therapy. However, increased toxicity of some regimens makes their general use difficult. Second-line CT is of value for selected patients with good performance status. Trastuzumab is the only targeted agent showing better survival when added to chemotherapy in HER2-driven tumors. CONCLUSIONS: With the introduction of new agents, management of advanced gastric cancer has experienced important changes. First and second-line CT improve survival in patients with good performance status. Future trials should address how to better select patients for new, targeted agents, based upon validated predictive biomarkers.

[Breast cancer metastases in the iris: does treatment modifies natural history of the illness?]. / Metástasis en iris de un carcinoma de mama: ¿modifica el tratamiento la historia natural de la enfermedad?

The 4-5% of the breast cancer patients have metastases in the eye. We present the case of a 30-year-old woman with an infiltrant duct carcinoma of the breast pT2N2M0 HER2 positive. Six months after primary radical treatment she had a systemic relapse with multiples metastatic sites, so several treatment with trastuzumab in combination with chemotherapy were started. After 4 years patient presented multiple white-coloured micronodules in the iris of the right eye. Only a 3-7.8% of ocular metastases are located in the iris. With mantenaince therapy with trastuzumab natural history of the illness has changed. Several studies had analyzed if metastases in the brain during treatment with trastuzumab have increased in comparison with the pretrastuzumab era. The infrequent presentation of metastases in the anterior uveal makes difficult to establish if it is an spontaneous fact or if it is favoured by trastuzumab treatment.

[Hyperammonaemic encephalopathy, possible complication after urinary diversion in radical cystectomy. Review of the literature with regard to a clinical case]. / La encefalopatia hiperamonémica, una posible complicación por derivación urinaria tras cistectomía radical. Revisión de la literatura a proposito de un caso.

INTRODUCTION: Radical cystectomy is an intervention with an important morbidity. Urinary diversion is a possible cause of metabolic complications like hyperammonaemic encephalopathy. CASE REPORT: We present the case of a patient treated with a radical cystectomy and modified ureterosigmoidostomy after diagnosis of bladder cancer. After surgery the patient presented in 4 ocasions recurrent episodic confusion. Laboratory and image tests were normal. Levels of seric ammonium was increased. After supportive treatment and hemodyalisis symptoms disappeared. Later patient was reoperated and a reconstruction to ileal conduit was made. DISCUSSION: Continent urinary diversions are advised due to important negative impact on quality of life produced by ileal conduit. However these diversions have several complications, like encephalopathy secondary to non-hepatic hyperammonaemia. Increased absortion of ammonium by intestinal tissue of the new-ladder induces encephalopathy. Early diagnosis of this complication is essencial in order to administer an effective treatment.

Parotid gland metastasis of a breast cancer.

Parotid gland metastases from malignant tumors are extremely rare. A 61-year-old woman was diagnosed with an early breast cancer with no expression of oestrogen and progesterone receptors. Five years later the patient presented a tumour in parotid gland. After total parotidectomy, microscopic analysis of the gland demonstrated an invasive duct carcinoma (IDC) with positive expression of oestrogen receptor. The patient was treated with chemotherapy followed by complementary local radiotherapy. Diagnosis of a metastasic tumour in parotid gland poses a challenge. In our case an immunohistochemical study of oestrogen receptor was fundamental to establish a diagnosis.

[Non-Hodgkin lymphomas with systemic presentation in patients with HIV infection. Clinical and prognostic factors in a series evaluated before the introduction of the highly active antiretroviral therapy (HAART)]. / Linfomas no hodgkinianos de presentación sistémica e infección por VIH. Análisis clínico y de factores pronóstico en una serie tratada antes de la introducción del tratamiento antirretrovírico de gran actividad.

PATIENTS AND METHOD: We studied patients with acquired human immunodeficiency virus (HIV) infection that developed non-Hodgkin's lymphoma (NHL) from January 1985 to October 2001. RESULTS: 44 patients (36 men, 8 women; median age 34 years) were included. Burkitt's lymphoma was diagnosed in 34%, and diffuse large cell B lymphoma in 29.5%. A history of AIDS diagnosis was detected in 20 cases (45%). International prognostic index (IPI) was 0-1 in 19 patients (43%), 2 in 12 (27%) and higher than 3 in 13 (30%). Chemotherapy was used in 64% of the patients, radiation therapy in 2% and both in 11%. Criteria for partial response were reached in 13 patients (29%), for complete remission in 2 (4%) and for stabilization in 1 (2%). Nine (20%) patients are alive (5 without disease), 22 (50%) died because of NHL, 5 (11%) died because of treatment associated toxicity and 8 died because of other causes. Median survival were 3 months, with a 1-year survival estimate of 24% and a 2-year survival estimate of 14%. In the univariate analysis of prognostic factors, IPI = 0-1 in comparison with IPI = 2-5 (p = 0.000), physical status (PS) < or = 2 (p = 0.021) and absence of B symptoms (p = 0.012) were significant. In the multivariate analysis, IPI = 0-1 was also significant (p = 0.000). CONCLUSIONS: Patients with HIV and NHL has multiple factors of poor prognosis. The survival is limited and chemotherapy toxicity is high. Patients with low IPI are a subgroup with better prognosis.

[Thirteen years' survival in a patient with isolated skin metastases of a gastric carcinoma. What kind of disease is that?]. / Supervivencia de trece años en un paciente con metástasis cutáneas aisladas de adenocarcinoma gãstrico. ¿Ante qué enfermedad nos encontramos?

Gastric adenocarcinoma is a high-lethality tumour and has a great tendency to recur. Liver and peritoneum are the places where the metastases are most frequently localised. We introduce the case of a woman diagnosed with gastric adenocarcinoma who showed isolated skin metastasis. There were an important number of recurrences (always in the skin). She was treated with radical surgery and later treated with different cytostatic schedules. The patient died 13 years after metastasis were diagnosed. With this case we wanted to pay attention to the role of the biologic prognostic factors of gastric carcinoma. The molecular biology of these tumours can explain the different evolution of the disease. Biologic prognostic factors can separate gastric carcinoma into different kinds of disease.

Pulmonary fibrosis induced by cyclophosphamide.

OBJECTIVE: To report a case of pulmonary fibrosis resulting from use of cyclophosphamide as chemotherapy to treat a patient with breast cancer. CASE SUMMARY: We describe the case of a 52-year-old woman with breast cancer who developed pulmonary fibrosis after four cycles of chemotherapy that included cyclophosphamide. Pulmonary function tests revealed the presence of a severe ventilatory restriction. The open lung biopsy revealed pulmonary fibrosis with vascular sclerosis and signs of pulmonary hypertension. DISCUSSION: Cyclophosphamide is an alkylating agent that has been associated with interstitial pneumonia and pulmonary fibrosis. The frequency of these unwanted effects is <1%. The clinical picture consists of the progressive appearance of dyspnea and a non-productive cough that progresses to severe pulmonary insufficiency. The risk factors described for these complications have been the use of chemotherapy regimens that include other drugs with known pulmonary toxicities, the cumulative total dose, the addition of radiotherapy, and the use of high doses of cyclophosphamide. CONCLUSIONS: Even though the frequency of pulmonary fibrosis in patients treated with cyclophosphamide-based chemotherapy regimens is low, the presence of dyspnea and an interstitial pattern in a patient makes it necessary to consider that possible drug toxicity. The open lung biopsy is the most accurate diagnostic technique for these cases. The discontinuation of cyclophosphamide and treatment with corticosteroids is usually followed by clinical recovery in approximately 50% of patients and, in some cases, reversal of the lung injury.