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Purpose:The phase III PROfound study (NCT02987543) evaluated olaparib versus abiraterone or enzalutamide (control) in metastatic castration-resistant prostate cancer (mCRPC) with tumor homologous recombination repair (HRR) gene alterations. We present exploratory analyses on the use of circulating tumor DNA (ctDNA) testing as an additional method to identify patients with mCRPC with HRR gene alterations who may be eligible for olaparib treatment.Patients and Methods:Plasma samples collected during screening in PROfound were retrospectively sequenced using the FoundationOne®Liquid CDx test for BRCA1, BRCA2 (BRCA), and ATM alterations in ctDNA. Only patients from Cohort A (BRCA/ATM alteration positive by tissue testing) were evaluated. We compared clinical outcomes, including radiographic progression-free survival (rPFS) between the ctDNA subgroup and Cohort A.Results:Of the 181 (73.9%) Cohort A patients who gave consent for plasma sample ctDNA testing, 139 (76.8%) yielded a result and BRCA/ATM alterations were identified in 111 (79.9%). Of these, 73 patients received olaparib and 38 received control. Patients’ baseline demographics and characteristics, and the prevalence of HRR alterations were comparable with the Cohort A intention-to-treat (ITT) population. rPFS was longer in the olaparib group versus control [median 7.4 vs. 3.5 months; hazard ratio (HR), 0.33; 95% confidence interval (CI), 0.21–0.53; nominal P < 0.0001], which is consistent with Cohort A ITT population (HR, 0.34; 95% CI, 0.25–0.47).Conclusions:When tumor tissue testing is not feasible or has failed, ctDNA testing may be a suitable alternative to identify patients with mCRPC carrying BRCA/ATM alterations who may benefit from olaparib treatment.

La miocardiopatía por estrés es una enfermedad infrecuente caracterizada por dolor precordial típico, elevación de las enzimas cardíacas y cambios electrocardiográficos, sin evidencia de enfermedad coronaria. Es transitoria y no tiene una causa clara desencadenante, aunque el estrés emocional es un factor que pareciera estar involucrado en la mayoría de los casos comunicados. Como consecuencia del desarrollo diagnóstico de enfermedades cardiovasculares, en los últimos 15 años aumentaron los casos, representando entre el 1-2% de los pacientes que se presentan con dolor precordial y cambios en el electrocardiograma. La toxicidad cardiológica por la quimioterapia y otros agentes antineoplásicos es conocida, pero el síndrome de takotsubo asociado a quimioterapia es poco frecuente y sólo se registran informes de casos. Presentamos tres pacientes con miocardiopatía por estrés asociado a quimioterapia.

Purpose: The phase III PROfound study (NCT02987543) evaluated olaparib versus abiraterone or enzalutamide (control) in metastatic castration-resistant prostate cancer (mCRPC) with tumor homologous recombination repair (HRR) gene alterations. We present exploratory analyses on the use of circulating tumor DNA (ctDNA) testing as an additional method to identify patients with mCRPC with HRR gene alterations who may be eligible for olaparib treatment. Patients and Methods: Plasma samples collected during screening in PROfound were retrospectively sequenced using the FoundationOne®Liquid CDx test for BRCA1, BRCA2 (BRCA), and ATM alterations in ctDNA. Only patients from Cohort A (BRCA/ATM alteration positive by tissue testing) were evaluated. We compared clinical outcomes, including radiographic progression-free survival (rPFS) between the ctDNA subgroup and Cohort A. Results: Of the 181 (73.9%) Cohort A patients who gave consent for plasma sample ctDNA testing, 139 (76.8%) yielded a result and BRCA/ATM alterations were identified in 111 (79.9%). Of these, 73 patients received olaparib and 38 received control. Patients’ baseline demographics and characteristics, and the prevalence of HRR alterations were comparable with the Cohort A intention-to-treat (ITT) population. rPFS was longer in the olaparib group versus control [median 7.4 vs. 3.5 months; hazard ratio (HR), 0.33; 95% confidence interval (CI), 0.21–0.53; nominal P < 0.0001], which is consistent with Cohort A ITT population (HR, 0.34; 95% CI, 0.25–0.47). Conclusions: When tumor tissue testing is not feasible or has failed, ctDNA testing may be a suitable alternative to identify patients with mCRPC carrying BRCA/ATM alterations who may benefit from olaparib treatment.

Aim: The aim of the study was to assess patient preference for the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PH FDC SC) in patients with HER2-positive early breast cancer in PHranceSCa (NCT03674112). Materials and methods: Patients who completed neoadjuvant P + H + chemotherapy + surgery were randomised 1:1 to three intravenous (IV) P + H cycles followed by three cycles of PH FDC SC or vice versa (crossover) and then chose subcutaneous (SC) injection or IV infusion to continue up to 18 cycles (continuation). Assessments were via patient and healthcare professional (HCP) questionnaires. Results: One hundred and sixty patients were randomised (cut-off: 24 February 2020); 136 (85.0%, 95% confidence interval: 78.5–90.2%) preferred SC; 22 (13.8%) preferred IV; 2 (1.3%) had no preference. The main reasons for SC preference were reduced clinic time (n = 119) and comfort during administration (n = 73). One hundred and forty-one patients (88.1%) were very satisfied/satisfied with SC injection versus 108 (67.5%) with IV infusion; 86.9% chose PH FDC SC continuation. HCP perceptions of median patient treatment room time ranged from 33.0–50.0 min with SC and 130.0–300.0 min with IV. Most adverse events (AEs) were grade 1/2 (no 4/5s); serious AE rates were low. AE rates before and after switching were similar (cycles 1–3 IV → cycles 4–6 SC: 77.5% → 72.5%; cycles 1–3 SC → cycles 4–6 IV: 77.5% → 63.8%). Conclusion: Most patients strongly preferred PH FDC SC over P + H IV. PH FDC SC was generally well tolerated, with no new safety signals (even when switching), and offers a quicker alternative to IV infusion.

Introduction Medical knowledge regarding preservation of fertility and pregnancy in patients with breast cancer (BC) is of interest. We, therefore, decided to conduct a survey on this issue among professionals involved in the treatment of BC in Argentina. Materials and methods A survey was conducted and sent by email to 3,412 contacts in the Argentine Mastology Society (Sociedad Argentina de Mastologia, or SAM) database, with responses from 396 physicians. The survey design was based on the Lambertini 2017 survey. To the author's knowledge, it is the first Argentine survey to address this issue. Results The frequency with which the impact of cancer treatment on the fertility of young patients was addressed by the respondent and referred to a fertility specialist was 'always' and 'almost always' in 86.8% and 78.5% of cases, respectively. Conclusions The level of knowledge is comparable to the data presented by other surveys. Membership in a Mastology Unit was associated with more current treatment. Continued work on the training of professionals is necessary to facilitate communication, information and guidance of patients of childbearing age who are going to have cancer treatment in order to advise them on fertility preservation, as well as the possibility of pregnancy after diagnosis of BC, and to be able to provide better care to those with BC associated with pregnancy.

Introduction Currently, the indication for neoadjuvant chemotherapy is increasing in the treatment of breast cancer. Variability in the expression of biomarkers following neoadjuvant treatment has been observed, which could be accompanied by changes in the adjuvant treatment. Objectives The primary objective was to evaluate the variability of biomarkers prior to and following neoadjuvant therapy. Secondary objectives were to determine which tumour subtype (as determined by immunohistochemical markers) most frequently achieved pathological complete response (pCR); whether the biomarker variation resulted in a change in immunophenotype and subsequently modification to the adjuvant treatment. Materials and methods A retrospective observational analysis was carried out on patients with a diagnosis of breast cancer who had neoadjuvant therapy prior to surgery in the Breast Care Service of the Buenos Aires British Hospital between January 2009 and June 2020. Results One hundred and seventy-two patients were included. The pCR rate was 28.5%. The tumour immunophenotype that achieved pCR most frequently was the hormone receptor negative /HER2+ group with a value of 85.2%. The analysis was carried out on the 123 patients with residual disease. The observed variability for oestrogen receptors (ER) was 8.9%, for progesterone receptors (PR), 29.9% and for HER2, 13.8%. These changes were statistically significant. There were changes to the tumour immunophenotype in 26 cases (21.1%) with modifications to the adjuvant treatment in nine of these (34.6%; 7.3% of all tumours with residual disease). Conclusions In this study, we observed statistically significant variability in the expression of ER, PR and HER2 prior to and following neoadjuvant treatment, which identified modifications in the tumour immunophenotype in 21.1%, and changes to the adjuvant treatment in 7.3% of all tumours with residual disease, justifying the re-assay of biomarkers in the surgical specimen.

BACKGROUND: The phase 3 trial CA184-043 evaluated radiotherapy to bone metastases followed by Ipilimumab or placebo in men with metastatic castrate-resistant prostate cancer (mCRPC) who had received docetaxel previously. In a prior analysis, the trial's primary endpoint (overall survival [OS]) was not improved significantly.OBJECTIVE: To report the final analysis of OS.DESIGN, SETTING, AND PARTICIPANTS: A total of 799 patients were randomized to receive a single dose of radiotherapy to one or more bone metastases followed by either Ipilimumab (n = 399) or placebo (n = 400).OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: OS was analyzed in the intention-to-treat population. Prespecified and exploratory subset analyses based on Kaplan-Meier/Cox methodology were performed.RESULTS AND LIMITATIONS: During an additional follow-up of approximately 2.4 yr since the primary analysis, 721/799 patients have died. Survival analysis showed crossing of the curves at 7-8 mo, followed by persistent separation of the curves beyond that point, favoring the ipilimumab arm. Given the lack of proportional hazards, a piecewise hazard model showed that the hazard ratio (HR) changed over time: the HR was 1.49 (95% confidence interval 1.12, 1.99) for 0-5 mo, 0.66 (0.51, 0.86) for 5-12 mo, and 0.66 (0.52, 0.84) beyond 12 mo. OS rates were higher in the ipilimumab versus placebo arms at 2 yr (25.2% vs 16.6%), 3 yr (15.3% vs 7.9%), 4 yr (10.1% vs 3.3%), and 5 yr (7.9% vs. 2.7%). Disease progression was the most frequent cause of death in both arms. In seven patients (1.8%) in the ipilimumab arm and one (0.3%) in the placebo arm, the primary cause of death was reported as study drug toxicity. No long-term safety signals were identified.CONCLUSIONS: In this preplanned long-term analysis, OS favored ipilimumab plus radiotherapy versus placebo plus radiotherapy for patients with postdocetaxel mCRPC. OS rates at 3, 4, and 5 yr were approximately two to three times higher in the ipilimumab arm.PATIENT SUMMARY: After longer follow-up, survival favored the group of men who received ipilimumab, with overall survival rates being two to three times higher at 3 yr and beyond.

El cáncer de próstata es el tumor más prevalente diagnosticado en el hombre y es el tercero en mortalidad luego del cáncer de pulmón y colorrectal en Argentina. Las diferentes terapias hormonales continúan siendo la principal modalidad de tratamiento sistémico en pacientes con cáncer de próstata avanzado.Aproximadamente el 10% de los pacientes con cáncer de próstata metastásico tienen mutaciones en línea germinal de genes que reparan el ADN y entre el 25-30% de la mortalidad por cáncer de próstata ocurre en la población con déficit de genes de reparación por recombinación homóloga (HRR). Este subgrupo presenta un curso clínico más agresivo con pobre pronóstico, pero en los últimos años se ha demostrado una mayor sensibilidad a sales de platino (cisplatino/carboplatino) e inhibidores de la poli (ADP-ribosa) polimerasa (PARP). El objetivo de nuestro trabajo fue analizar las características clínico-patológicas de los pacientes con cáncer metastásico de próstata resistente a la castración (mCRPC) y que presentaron alteraciones en genes de HRR. En aquellos con mutaciones en genes de HRR se observa una tendencia de diagnóstico a edades más tempranas, mayor frecuencia de antecedentes oncológicos familiares, mayor compromiso visceral y menor intervalo libre de progresión a terapia de deprivación androgénica que en los no portadores de genes de HRR.

27 Background: ctDNA testing offers additional opportunities for homologous recombination repair (HRR) gene alteration determination in patients who are not able to access tumor tissue testing. Alteration testing in ctDNA, for BRCA1, BRCA2 and ATM alterations was performed retrospectively in the PROfound study (phase 3 trial of olaparib versus physician’s choice of abiraterone or enzalutamide in men with HRR gene-mutated mCRPC [NCT02987543]). Methods: ctDNA samples were sequenced at FMI, using the FoundationOne Liquid CDx assay for alterations in BRCA1, BRCA2 (BRCA) and ATM, using plasma samples collected during screening in PROfound. Only patients who consented and provided plasma samples from Cohort A (BRCA/ ATM alteration positive by tissue testing) were tested for ctDNA alterations. Radiographic progression-free survival (rPFS) assessed by blinded independent central review (BICR) in patients positive for alterations in ctDNA was analysed via stratified log-rank test. Additional efficacy endpoints (Objective Response Rate [ORR], Overall Survival[OS]) were also assessed. Results: In total, 181/245 (73.9%) Cohort A patients consented and provided a plasma sample for ctDNA testing, of which 139/181 (76.8%) had a ctDNA result reported (either mutation positive or mutation negative) and 42 patient samples failed testing due to insufficient DNA yield or a technical failure of the test.BRCA/ ATM alterations were identified in111/139 (79.9%) patients and 28/139 patients did not report a BRCA/ATM mutation either due to lack of ctDNA shedding from the tumour or ctDNA levels below the sensitivity of the assay. Patients who carried BRCA/ ATM ctDNA alterations had comparable demography, baseline characteristics and proportions of BRCA1, BRCA2 and ATM mutated patients to the overall Cohort A patients. rPFS by BICR results, in patients with BRCA/ ATM alterations in ctDNA, are presented in the Table. Key secondary efficacy endpoints (ORR, OS) will also be reported for ctDNA alteration positive patients. Conclusions: ctDNA testing in patients with mCRPC is feasible and most, but not all patients have concordant results. Patients who were positive for alterations in BRCA1, BRCA2 or ATM showed a consistent rPFS improvement (hazard ratio [HR] 0.33 [0.21, 0.53]) when compared with the ITT population identified by tumor tissue testing (HR 0.34 [0.25, 0.47]). This suggests that using ctDNA to identify patients carrying BRCA1, BRCA2 or ATM alterations who will benefit from olaparib may be beneficial. Clinical trial information: NCT02987543. [Table: see text]

Summary Background Nanoliposomal irinotecan showed activity in a phase 2 study in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapies. We assessed the effect of nanoliposomal irinotecan alone or combined with fluorouracil and folinic acid in a phase 3 trial in this population. Methods We did a global, phase 3, randomised, open-label trial at 76 sites in 14 countries. Eligible patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy were randomly assigned (1:1) using an interactive web response system at a central location to receive either nanoliposomal irinotecan monotherapy (120 mg/m 2 every 3 weeks, equivalent to 100 mg/m 2 of irinotecan base) or fluorouracil and folinic acid. A third arm consisting of nanoliposomal irinotecan (80 mg/m 2 , equivalent to 70 mg/m 2 of irinotecan base) with fluorouracil and folinic acid every 2 weeks was added later (1:1:1), in a protocol amendment. Randomisation was stratified by baseline albumin, Karnofsky performance status, and ethnic origin. Treatment was continued until disease progression or intolerable toxic effects. The primary endpoint was overall survival, assessed in the intention-to-treat population. The primary analysis was planned after 305 events. Safety was assessed in all patients who had received study drug. This trial is registered at ClinicalTrials.gov, number NCT01494506. Findings Between Jan 11, 2012, and Sept 11, 2013, 417 patients were randomly assigned either nanoliposomal irinotecan plus fluorouracil and folinic acid (n=117), nanoliposomal irinotecan monotherapy (n=151), or fluorouracil and folinic acid (n=149). After 313 events, median overall survival in patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid was 6·1 months (95% CI 4·8–8·9) vs 4·2 months (3·3–5·3) with fluorouracil and folinic acid (hazard ratio 0·67, 95% CI 0·49–0·92; p=0·012). Median overall survival did not differ between patients assigned nanoliposomal irinotecan monotherapy and those allocated fluorouracil and folinic acid (4·9 months [4·2–5·6] vs 4·2 months [3·6–4·9]; 0·99, 0·77–1·28; p=0·94). The grade 3 or 4 adverse events that occurred most frequently in the 117 patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid were neutropenia (32 [27%]), diarrhoea (15 [13%]), vomiting (13 [11%]), and fatigue (16 [14%]). Interpretation Nanoliposomal irinotecan in combination with fluorouracil and folinic acid extends survival with a manageable safety profile in patients with metastatic pancreatic ductal adenocarcinoma who previously received gemcitabine-based therapy. This agent represents a new treatment option for this population. Funding Merrimack Pharmaceuticals.

El trastuzumab es un anticuerpo monoclonal dirigido contra el receptor del factor de crecimiento epidérmico humano (Her2), el cual se encuentra sobreexpresado en aproximadamente el 20% del cáncer de mama invasivo. El trastuzumab es un claro ejemplo de exitoso desarrollo de terapia “blanco específica” en oncología y actualmente se encuentra aprobado para su uso terapéutico en cáncer de mama Her2+ tanto en enfermedad avanzada como con criterio adyuvante. Sin embargo, alrededor del 50% de las pacientes con cáncer de mama Her2+ no se benefician de las terapias basadas en trastuzumab. El entendimiento de los mecanismos de acción y de resistencia al trastuzumab es crucial para el desarrollo de nuevas estrategias de tratamiento. Los mecanismos de resistencia al trastuzumab se pueden agrupar en 4 categorías principales: A. Obstáculos para la unión del trastuzumab al dominio extracelular del Her2. B. Activación de las vías de traducción de señales río abajo del Her2. C. Activación de vías alternativas del Her2. D. Fallas del sistema inmunitario para destruir las células tumorales. Esta revisión resume las evidencias preclínicas y clínicas acerca de los mecanismos de acción y resistencia al trastuzumab y también discute el desarrollo de nuevas drogas antiHer2 y sus posibles implicancias clínicas.

Objectives: Irinotecan or oxaliplatin combined with 5-fluorouracil (5-FU) ± folinic acid (FA) has changed the treatment standards for metastatic colorectal cancer (CRC). The oxaliplatin and irinotecan combination has reported consistent activity. The purpose of this phase II study was to assess the efficacy and safety of the simultaneous administration of a triple chemotherapy combination of oxaliplatin, irinotecan, 5-FU bolus, and FA. Materials and Methods: Eligible patients had metastatic CRC with no prior oxaliplatin or irinotecan-based chemotherapy. Treatment consisted of oxaliplatin 85 mg/m2 followed by irinotecan 150 mg/m2, repeated every 15 days, with 5-FU 500 mg/m2 bolus and FA 20 mg/m2 on days 1, 8, and 15. An early amendment suppressed the day 8 5-FU/FA. Results: Twenty-six eligible treated patients receiving 253 doses were assessed for toxicity. Myelosuppression was the most frequent toxicity; grade 3 to 4 neutropenia and febrile neutropenia occurred in 50% and 15% of patients, respectively. The treatment schedule modification, omitting the 5-FU dosing on day 8, considerably improved treatment compliance, reducing the incidence of febrile neutropenia, diarrhea, and asthenia. Results: Among the 25 patients evaluable for efficacy, 10 had objective responses including 1 complete response (CR) (4%) and 9 partial responses (PR) (36%), giving an overall response rate of 40%. Median time to progression was 6.20 months [95% confidence interval (CI), 5.44–6.96]. Median overall survival was 12.95 months. Conclusions: The administration of a triple combination produced promising objective responses with acceptable toxicity but does not seem to produce an evident benefit in time-related parameters.